PROJECT SUMMARY/ABSTRACT Somatosensory neurons that innervate the skin and muscle play an essential role in sensing touch, pain, and proprioception. The same type of sensory neurons innervates other organs that experience frequent mechanical stimulation. This list of such organs/tissues includes bone, teeth, lung, vasculature, stomach, and bladder. Anatomically, cranial ganglia (including trigeminal) innervate the head, while nodose/jugular and dorsal root ganglia (DRG) innervate the rest of the body. The role of the mechanically activated (MA) non-selective cation channel Piezo2 in DRGs for sensing touch and proprioception is well established. However, much less is known about the role of Piezo2 (and mechanotransduction in general) in other sensory ganglia that innervate the craniofacial region and other internal organs. For example, repetitive and wide-ranging mechanical forces are experienced by our respiratory system. Lung stretch is sensed by neurons with their cell bodies in the nodose/jugular, trigeminal, and thoracic DRGs. Mechanically-driven reflexes are thought to be crucial for proper lung function; however, the precise physiological significance and molecular mechanism of mechanotransduction within the lung remains obscure. In preliminary data presented in this proposal, we show that Piezo2 is expressed in neurons innervating the airways. We further show that global and sensory neuronspecific ablation of Piezo2 causes symptoms of respiratory distress. Building on the preliminary data presented here, we will investigate the role of Piezo2 in respiration and in various craniofacial tissues.